The present invention concerns a new process for the reductive alkylation of secondary amines using hydrosilane with applications to the preparation of imidazole-containing benzodiazepines, inhibitors of farnesyl protein transferase which find utility in the treatment of a variety of cancers and other diseases (Ding, C. Z.; Hunt, J. T.; Kim, S.-h.; Mitt, T.; Bhide, R.; Leftheris, K. WO 9730992; Chem. Abstr. 1998,127, 278213).
Many methods have been previously reported for the reductive alkylation of secondary amines with carbonyl compounds in the presence of a reducing agent. The reducing agent includes: zinc (Lockemann, G. DE 503113; Chem. Abstr. 1931, 25, 522), H.sub.2 /Pd(or Pt, Ni) (Emerson, W. S. Org. React. 1948, 4,174; Schaus, J. M.; Huser, D. L.; Titus, R. D. Synth. Commun. 1990, 20, 3553), selenophenol (Fujimori, K.; Yoshimoto, H.; Oae, S. Tetrahedron Lett. 1980, 21, 3385), NaBH.sub.4 (Verardo, G.; Giumanini, A. G.; Strazzolini, P. Synth. Commun. 1994, 24, 609), and NaCNBH.sub.3 (Lee, M.; Garbiras, B. J. Synth. Commun. 1994, 24, 3129). All these reducing agents suffer one or more drawbacks. They are either toxic such as selenophenol and NaCNBH.sub.3, or are not selective such as zinc, H.sub.2)Pd(or Pt, Ni) and NaBH.sub.4 since a number of other reducible groups could be affected by these reagents. NaBH(OAc).sub.3 was subsequently introduced to address these problems (Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996,61, 3849) and this reagent was used in the preparation of the aforementioned imidazole-containing benzodiazepine compounds (Ding, C. Z.; Hunt, J. T.; Kim, S.-h.; Mitt, T.; Bhide, R.; Leftheris, K., WO 9730992; Chem. Abstr. 1998, 127, 278213). Although the desired products were obtained from 1 H-benzodiazepine starting materials, a large excess of aldehyde was required for a satisfactory conversion. In addition, expensive chromatographic separation of products was necessary which rendered this method not amenable to large scale preparation.
Reduction of imines preformed from primary anilines and aldehydes to secondary anilines with Et.sub.3 SiH/TFA has been previously reported (Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633; Loim, N. M. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1968,1345). Reduction of the preformed aminal from secondary amine and formaldehyde to give tertiary amine using Et.sub.3 SiH/TFA has also been disclosed (Beulshausen, T.; Groth, U.; Schoellkopf, U. Liebigs Ann. Chem. 1992, 523). However, it remains as a question whether the direct reductive alkylation of a secondary amine with an aldehyde using Et.sub.3 SiH/TFA would work, since it was well documented that aldehydes react readily with Et.sub.3 SiH/TFA to give the corresponding alcohols and even methylenes (Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633; West, C. T.; Donnelly, S. J.; Kooistra, D. A.; Doyle, M. P. J. Org. Chem. 1973, 38, 2675).